Peroxisome proliferators activated receptor gamma, like estrogen receptor alpha, is a nuclear receptor that is highly expressed in breast cancer. However, as opposed to ER alpha ligands which activate proliferation, PPAR gamma ligands have been shown to induce differentiation in breast cancer cells. Furthermore, PPAR and ER have been shown to crosstalk. The exact mechanism of this interaction, however, is unclear. Elucidation of the interaction between ER and PPAR will be critical in the understanding of hormone receptor crosstalk in hormone dependent breast cancer and its application in the development of improved treatments. Our objective is to identify novel therapeutic targets for hormone dependent breast cancer by defining mechanism(s) involved in ER/PPAR crosstalk. Aim 1 will test the hypothesis that the selective regulation of critical target genes involved in breast cancer is dependent on ER/PPAR crosstalk. Aim 2 will test the hypothesis that a protein-protein interaction mediates ER/PPAR crosstalk in breast cancer cells. Aim 3 will test the hypothesis that activation of the MAPK (MEK) phosphorylation cascade contributes to ER/PPAR crosstalk in breast cancer by altering receptor mediated gene expression and cell function.